{"uniprot":"Q8IZF4","gene":"ADGRG5","name":"Adhesion G-protein coupled receptor G5","organism":"Homo sapiens (Human)","status":"dark","length":528,"sequence":"MDHCGALFLCLCLLTLQNATTETWEELLSYMENMQVSRGRSSVFSSRQLHQLEQMLLNTSFPGYNLTLQTPTIQSLAFKLSCDFSGLSLTSATLKRVPQAGGQHARGQHAMQFPAELTRDACKTRPRELRLICIYFSNTHFFKDENNSSLLNNYVLGAQLSHGHVNNLRDPVNISFWHNQSLEGYTLTCVFWKEGARKQPWGGWSPEGCRTEQPSHSQVLCRCNHLTYFAVLMQLSPALVPAELLAPLTYISLVGCSISIVASLITVLLHFHFRKQSDSLTRIHMNLHASVLLLNIAFLLSPAFAMSPVPGSACTALAAALHYALLSCLTWMAIEGFNLYLLLGRVYNIYIRRYVFKLGVLGWGAPALLVLLSLSVKSSVYGPCTIPVFDSWENGTGFQNMSICWVRSPVVHSVLVMGYGGLTSLFNLVVLAWALWTLRRLRERADAPSVRACHDTVTVLGLTVLLGTTWALAFFSFGVFLLPQLFLFTILNSLYGFFLFLWFCSQRCRSEAEAKAQIEAFSSSQTTQ","function_summary":"A human class B orphan G protein-coupled receptor that resides at the cell surface as a multi-pass membrane protein. Its N-terminal ectodomain undergoes autoproteolysis and forms a tension-sensitive module that communicates with a seven-helix signaling core, enabling coupling to heterotrimeric G proteins. Through this architecture, it initiates canonical GPCR signaling cascades despite an as-yet unidentified extracellular ligand, with ectodomain mechanics and membrane-embedded helices jointly controlling activation and downstream pathway engagement.","plain_language":"ADGRG5 has barely been studied. The model's best guess: A human class B orphan G protein-coupled receptor that resides at the cell surface as a multi-pass membrane protein. Its N-terminal ectodomain undergoes autoproteolysis and forms a tension-sensitive module that communicates with a seven-helix signaling core, enabling coupling to heterotrimeric G proteins.","uniprot_summary":"Orphan receptor.","go_terms":{"molecular_function":[{"id":"GO:0004930","label":"G protein-coupled receptor activity"}],"biological_process":[{"id":"GO:0007186","label":"G protein-coupled receptor signaling pathway"}],"cellular_component":[{"id":"GO:0016020","label":"membrane"}]},"interpro":[{"id":"IPR046338","name":"GAIN domain superfamily","type":"homologous_superfamily","start":84,"end":238},{"id":"IPR057244","name":"GAIN, subdomain B","type":"domain","start":78,"end":239},{"id":"IPR017981","name":"GPCR, family 2-like, 7TM","type":"domain","start":247,"end":507},{"id":"IPR003910","name":"GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5","type":"family","start":163,"end":179},{"id":"IPR003910","name":"GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5","type":"family","start":181,"end":194},{"id":"IPR000832","name":"GPCR, family 2, secretin-like","type":"family","start":250,"end":274},{"id":"IPR000832","name":"GPCR, family 2, secretin-like","type":"family","start":282,"end":306},{"id":"IPR000832","name":"GPCR, family 2, secretin-like","type":"family","start":316,"end":339},{"id":"IPR003910","name":"GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5","type":"family","start":340,"end":354},{"id":"IPR000832","name":"GPCR, family 2, secretin-like","type":"family","start":355,"end":380},{"id":"IPR003910","name":"GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5","type":"family","start":400,"end":418},{"id":"IPR000832","name":"GPCR, family 2, secretin-like","type":"family","start":485,"end":506},{"id":"IPR000203","name":"GPS motif","type":"conserved_site","start":96,"end":238}],"reasoning":"I begin with the InterPro architecture. The N-terminal ectodomain is defined by IPR046338 (GAIN domain superfamily, residues 84–238) and IPR057244 (GAIN, subdomain B, residues 78–239), which together specify a canonical adhesion-protein-like fold used by class B (secretin-like) GPCRs to undergo autoproteolysis and mechanical coupling. Embedded within this region is IPR000203 (GPS motif, residues 96–238), a conserved autoproteolytic site that cleaves the GAIN-containing ectodomain into N-terminal and C-terminal fragments that remain associated. Immediately downstream, the seven-transmembrane signaling core is captured by IPR017981 (GPCR, family 2-like, 7TM, residues 247–507), establishing a class B GPCR scaffold. Multiple family signatures reinforce this identity: IPR000832 (GPCR, family 2, secretin-like, residues 250–274; 282–306; 316–339; 355–380; 485–506) collectively mark conserved sequence features of secretin-like receptors across the helical bundle. Additional lineage-specific markers IPR003910 (GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5, residues 163–179; 181–194; 340–354; 400–418) tie this receptor to the orphan clade that includes GPR1/3/5-like architectures. The ordered layout—GAIN/GPS ectodomain followed by a class B seven-helix core—causally dictates a GPCR that signals through heterotrimeric G proteins.\n\nThis architecture enforces GO:0004930 G protein-coupled receptor activity as the molecular function: the 7TM bundle (IPR017981) forms the G protein coupling interface, while the GAIN/GPS module modulates activation by controlling ectodomain–TM communication. Consequently, the signaling role maps to GO:0007186 G protein-coupled receptor signaling pathway as the biological process, where ligand- or context-dependent coupling triggers downstream cascades. The presence of a long multipass transmembrane core and the explicit seven-helix topology places the protein at the cell surface, consistent with GO:0016020 membrane and with a multi-pass membrane localization.\n\nMechanistically, the GAIN domain and GPS motif drive autoproteolysis that yields an N-terminal fragment tethered to the seven-helix core. This cleavage creates a tension-sensitive switch: extracellular forces or ligand-induced ectodomain rearrangements propagate through the GAIN fold to the helical bundle, biasing the active state that recruits and activates heterotrimeric G proteins. The class B-like hallmarks and orphan clade markers suggest a poorly characterized extracellular ligand—potentially a matrix or peptide cue—sensing pathway that is transduced into intracellular signaling via Gα/βγ exchange and effector modulation.\n\nFrom this model, I hypothesize that the receptor resides at the plasma membrane as a multi-pass complex, where it assembles transient signaling modules. Likely partners include heterotrimeric G proteins (Gs, Gi/o, or Gq/11 families), β-arrestins that bind and regulate desensitization and endocytosis, and GPCR kinases that tune signaling duration. The GAIN/GPS ectodomain further implies association with extracellular matrix or adhesion-associated proteins that bias activation by mechanical or ligand cues.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q8IZF4.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q8IZF4"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q8IZF4/entry","atlas":"/p/Q8IZF4"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}